1. Field of the Invention
This invention is directed to synthesis, starting from thebaine, of neopinone dialkyl ketals, neopinone or codeinone, each of which is convertible to codeine by conventional processes.
2. Description of Prior Art
Codeine, widely used as a pain-killer and cough suppressant, has conventionally been prepared by methylation of morphine, which is also traditionally used as the raw material for the illicit drug heroin. Morphine is obtained by extraction of opium or poppy straw from the opium poppy (Papaver somniferum), of which commercial cultivation is illegal in the United States. Because no commercially viable total synthesis of codeine has been devised and because of the uncertainties of relying on foreign sources of intermediates for codeine, it is apparent that development of alternative routes to codeine using domestically available non-addictive intermediates is of considerable significance.
Thebaine, a product isolated from the perennial poppy P. bracteatum, which does not produce morphine, would be an acceptable alternative to morphine as an intermediate for codeine. An additional advantage of using thebaine as an intermediate is that thebaine is not readily converted to morphine and thence to heroin. Moreover, the cultivation of P. bracteatum is not proscribed.
Krausz, in U.S. Pat. No. 3,112,323, and Gavard et al., Bull. Soc. Chim. France (1965) at 486-490, have described the conversion of thebaine (1) to codeine by treatment with anhydrous HBr to produce a product which is dehydrobromated to a mixture containing codeinone (4), reduction of which gives codeine (6).
Rapoport et al., in U.S. Pat. Nos. 4,054,566 and 4,110,329, and Barber et al., J. Med. Chem., vol. 19 (1976) at 1175-1180, describe the conversion of thebaine (1) to a mercurated neopinone dimethyl ketal (3, R is CH.sub.3), which can be hydrolyzed by formic acid to a mixture of codeinone (4) and neopinone (5), which mixture can be converted to codeine (2). ##STR1##
Barber et al., supra, also disclosed that thebaine, treated with an excess of mercuric salt in refluxing aqueous tetrahydrofuran gave a mixture of neopinone and codeinone (1:3 ratio) in 38% yield.
The conversion of thebaine to a mixture of codeinone, neopinone and/or neopinone ketal by mercury-catalyzed or photochemical routes has been disclosed by the applicants, J. Org. Chem., vol. 44 (1979), at 1567-1569, incorporated herein by reference.